Two Novel Palbociclib-Resorcinol and Palbociclib-Orcinol Cocrystals with Enhanced Solubility and Dissolution Rate

Palbociclib (PAL) is an effective anti-breast cancer drug, but its use has been partly restricted due to poor bioavailability (resulting from extremely low water solubility) and serious adverse reactions. In this study, two cocrystals of PAL with resorcinol (RES) or orcinol (ORC) were prepared by evaporation crystallization to enhance their solubility. The cocrystals were characterized by single crystal X-ray diffraction, Hirshfeld surface analysis, powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform infrared and scanning electron microscopy. The intrinsic dissolution rates of the PAL cocrystals were determined in three different dissolution media (pH 1.0, pH 4.5 and pH 6.8), and both cocrystals showed improved dissolution rates at pH 1.0 and pH 6.8 in comparison to the parent drug. In addition, the cocrystals increased the solubility of PAL at pH 6.8 by 2–3 times and showed good stabilities in both the accelerated stability testing and stress testing. The PAL-RES cocrystal also exhibited an improved relative bioavailability (1.24 times) than PAL in vivo pharmacokinetics in rats. Moreover, the in vitro cytotoxicity assay of PAL-RES showed an increased IC50 value for normal cells, suggesting a better biosafety profile than PAL. Co-crystallization may represent a promising strategy for improving the physicochemical properties of PAL with better pharmacokinetics.

Origin of Lithium–Potassium-Rich Brines in the JianghanBasin, South China: Constraints by Water–Rock Reactions of Mesozoic–Cenozoic Igneous Rocks

A large number of lithium–potassium-rich brines have been found in Paleocene reservoirs in the Jianghan Basin, South China. First, the brines have exceptionally high lithium and potassium contents that are even higher than those in other closed basins on the Tibetan Plateau. Second, the enriched brines are widely distributed in the center of the basin. The Mesozoic and Cenozoic igneous rocks in the Jiangling depression are mainly basalt and granite, and their distribution area exceeds 50% of the basin. The large basalt body provided a thermal source for the water–rock reaction. The igneous rocks in the study area could have provided ore-forming elements, such as lithium and potassium, for the brine. A static immersion experiment at room temperature shows that fluids with certain salinities are more likely to activate K ions in basalt. However, weakly alkaline solutions more easily dissolve K. High-temperature water–rock experiments show that the dissolution rates of Ca, Mg, and Sr decrease with increasing temperature, while the dissolution rates of K and Li first increase and then decrease with increasing temperature. The dissolution of K and Li is easier when saline fluid reacts with volcanic rock. The dissolution rate of K is higher than that of Li in basalt, and the dissolution rate of Li is higher than that of K in granite. Compared with the results at normal temperatures, the ability of the fluid to leach elements at higher temperatures is significantly enhanced. Temperature is the main factor controlling the ability of fluid to leach elements. High-salinity fluid is the main carrier of ore-forming elements. According to the water–rock experiments, the mineral composition of the ancient brine in the Jiangling depression that formed during the Paleocene is consistent with that of the ore-rich brine found today, but different by a few orders of magnitude, indicating that the formation of lithium–potassium-rich brines requires a long time. The water–rock reaction is one of the important processes of brine formation, and surface evaporation and concentration are the main mechanisms of brine mineralization.

Evaluation of the corrosion behavior of modern spent nuclear fuels under repository conditions

In Germany it is planned to directly dispose spent nuclear fuel (SNF) from nuclear power plants together with other high-level radioactive wastes (HLW) from former SNF reprocessing (e.g., vitrified waste), in a deep geological repository for heat-generating wastes – the siting process for this repository was started in 2017 and is ongoing. Based on several decades of research, development, and demonstration (RD&D) it is generally accepted at the technical and scientific level that direct disposal of HLW and SNF in deep mined geological repositories is the safest and most sustainable option (CEC, 2011; IAEA, 2004). The current efforts to improve the performance and accident tolerance of fuels in nuclear power generation resulted in an increased utilization of a variety of new types of light-water reactor (LWR) fuels such as fuels doped with Cr, Al, and Si. This doping leads to a significant change of the microstructure of the fuel matrix. The corrosion behavior of these types of fuels under conditions relevant to deep geological disposal has hardly been studied so far; however, this is of crucial importance as the development of a robust safety case for deep geological disposal of SNF requires a solid understanding of its dissolution behavior over very long time scales (up to 1 million years). To fill this knowledge gap, additional systematic studies on modern doped UO2 fuels were needed. Corrosion experiments with SNF cannot entirely unravel all of the various concurring effects of the dissolution mechanism due to the chemical and structural complexity of SNF and its high beta and gamma radiation field during the first 1000 years; moreover, technical restrictions only allow a very limited number of experiments. Therefore, within the EU-DisCo project (https://www.disco-h2020.eu, last access: 11 October 2021), a very ambitious programme of corrosion studies on irradiated Cr and Al/Cr doped fuels was carried out, which was complemented by systematic single-effect dissolution studies (e.g., with respect to doping level, grain size and thermodynamic aspects) performed on carefully prepared and characterized, simplified UO2-based model materials. Here, we present recent results on the dissolution behavior of tailor-made UO2 model materials in accelerated static batch experiments using H2O2 as simulant for radiolytic oxidants, present in long-term disposal scenarios for SNF in failed container conditions due to the alpha irradiation of water. In these dissolution experiments pure UO2 reference pellets exhibiting different densities and grain sizes, as well as Cr-doped UO2 pellets with various Cr-doping levels, produced using different doping methods having different grain sizes, were used. In addition, Nd-doped and industrially produced Cr- and Cr/Nd-doped UO2 pellets were used to determine the influence of these parameters on the dissolution rates. The dissolution experiments were performed under strictly controlled conditions with respect to exclusion of oxygen, temperature control, and exclusion of light. This bottom-up approach was followed to understand how the addition of Cr-oxide into the fuel matrix affects SNF dissolution behavior under repository relevant conditions. The results of the dissolution experiments performed with real SNF and the model materials obtained by the DisCo partners build the basis for numerical simulations on the dissolution behavior of modern SNF. First results of the data evaluation indicate that the addition of dopants and the consequential modification of the fuel matrix does not lead to a significant change of the dissolution behavior of these fuels under repository relevant conditions compared to standard SNF (i.e. dissolution rates agree within an order of magnitude).

Cosmogenic nuclide and solute flux data from central Cuba emphasize the importance of both physical and chemical denudation in highly weathered landscapes

We consider measurements of both in situ produced cosmogenic nuclides and dissolved load flux to characterize the processes and pace of landscape change in central Cuba. The tropical landscape of Cuba is losing mass in multiple ways, making it difficult to quantify total denudation rates and thus to assess the impact of agricultural practices on rates of contemporary landscape change. Long-term sediment generation rates inferred from 26Al and 10Be concentrations in quartz extracted from central Cuban river sand range from 3.7–182 tons km−2 yr−1 (mean = 62, median = 57). Rock dissolution rates (24–154 tons km−2 yr−1; mean = 84, median = 78) inferred from stream solute loads exceed measured cosmogenic nuclide-derived sediment generation rates in 15 of 22 basins, indicating significant landscape-scale mass loss not reflected in the cosmogenic nuclide measurements. 26Al / 10Be ratios lower than that of surface production are consistent with the presence of a deep, mixed, regolith layer in the five basins that have the greatest disagreement between rock dissolution rates (high) and sediment generation rates inferred from cosmogenic nuclide concentrations (low). Our data show that accounting for the contribution of mineral dissolution at depth in calculations of total denudation is particularly important in the humid tropics, where dissolved load fluxes are high, and where mineral dissolution can occur many meters below the surface, beyond the penetration depth of most cosmic rays and thus the production of most cosmogenic nuclides. Relying on cosmogenic nuclide data or stream solute fluxes alone would both lead to underestimates of total landscape denudation in the central Cuba, emphasizing the importance of combining these approaches to fully capture mass loss in tropical landscapes.

Estimating the activation energy of bond hydrolysis by time-resolved weighing of dissolving crystals

Bond-breaking activation energy EB is nowadays a key parameter for understanding and modeling crystal dissolution processes. However, a methodology to estimate EB based on classical dissolution experiments still does not exist. We developed a new method based on the calibration of a Kossel type dissolution model on measured dissolution rates obtained by mass (or volume) variations over time. The dissolution model does not depend on the geometry of the crystal surface but only on the density of the different types of sites (kink, step, terrace, bulk). The calibration method was applied to different experimental setups (flow through and batch) with different ways of estimating the dissolution rates (solute concentration in the fluid, surface topography) for calcite crystals. Despite the variety of experimental conditions, the estimated bond-breaking activation energies were very close to each other (between 31 and 35 kJ/mol) and in good agreement with ab initio calculations.